Environmental stressors are thought to trigger the onset or relapse of schizophrenia in vulnerable individuals. Symptoms include sensory flooding and cognitive fragmentation, which are the result of sensorimotor gating deficits. Sensorimotor gating can be measured using a quantitative test that assesses reduction of the startle response to an acoustic pulse stimulus after presentation of a weaker prepulse stimulus. Such prepulse inhibition of the acoustic startle response (PPI) is disrupted in patients with schizophrenia and in rats with dopaminergic abnormalities in the nucleus accumbens and/or prelimbic and infralimbic prefrontal cortex. A stressful social interaction between conspecific animals causes such dopamine dysfunction, and disrupts PPI. The long-range goal of this project is to determine the cellular and molecular mechanisms by which social stress can produce symptoms of schizophrenia. An animal model of sensorimotor gating will be used to examine the neurobiological responses leading to PPI disruption after repeated social stress exposure, initially focusing on the role of prelimbic/infralimbic cortex. The specific aims of the project are (1) to determine the time course of PPI disruption induced by repeated social stress exposure, elucidating the involvement of D2-like receptors in this abnormal behavior, (2) to ascertain whether repeated social stress reduces tonic dopamine activity in prelimbic/infralimbic cortex, (3) to quantify and characterize the persistent expression of Fos-related antigen in prelimbic/infralimbic cortex following repeated social stress, (4) to determine whether dopamine depletion in prelimbic/infralimbic cortex has the same behavioral and biochemical effects as stress, and whether selective dopamine receptor stimulation in the same region relieves PPI disruption after repeated social stress, and (5) to characterize the neuroanatomical connections of cortical neurons expressing Fos-related antigens after repeated social stress exposure. Together, these studies will produce novel data on the cellular and molecular effects of a salient social stressor, which causes long-lasting sensorimotor gating deficits in rodents, and may trigger the onset or relapse of schizophrenia in patients